GRHL3 – Van der Woude Syndrome

Grainyhead-like transcription factor 3 (GRHL3) is a critical regulator of epithelial differentiation, and heterozygous mutations in GRHL3 underlie Van der Woude syndrome (VWS), an autosomal dominant disorder characterized by paramedian lower lip pits and orofacial clefts. Clinical recognition of isolated or atypical lip pits, including rare upper lip pits, should prompt targeted sequencing of GRHL3 alongside IRF6 (PMID:38861357).

Genetic analyses in 45 IRF6-negative VWS families identified coding mutations in GRHL3 in 8 unrelated families, revealing a spectrum of variant classes including truncating, splice-site, and missense alleles. One recurrent truncating allele observed was c.899G>A (p.Trp300Ter) (PMID:24360809). Segregation of these variants with disease across multiple pedigrees supports a dominant inheritance mechanism.

Segregation analysis demonstrated co-segregation of GRHL3 variants with VWS in 8 families, confirming pathogenicity through family studies and meeting criteria for strong genetic evidence (PMID:24360809). No founder effect has been reported to date, and allele frequencies remain extremely low in population databases.

Functional assays in zebrafish periderm and Grhl3-null mouse models corroborate a dominant-negative mechanism: patient-specific GRHL3 mutations abrogate periderm formation in zebrafish and 17% of Grhl3-deficient mice develop cleft palate, faithfully recapitulating human VWS phenotypes (PMID:24360809). These experiments establish mechanistic concordance between human and animal data.

In contrast, two common GRHL3 missense SNPs (rs2486668 and rs545809) showed no association with non-syndromic cleft palate in a Han Chinese cohort, underscoring that rare, high-penetrance variants rather than common polymorphisms drive VWS risk (PMID:27459192).

Integration of genetic and experimental data yields a strong gene–disease association: heterozygous GRHL3 variants cause peridermopathy, leading to lip pits and orofacial clefts in VWS. Diagnosis of VWS should include GRHL3 sequencing for IRF6-negative cases, and functional data support clinical interpretation of novel GRHL3 alleles.

Key Take-home: GRHL3 haploinsufficiency and dominant-negative variants are established causes of Van der Woude syndrome, with direct implications for genetic testing and family counseling.

References

• American Journal of Human Genetics • 2014 • Dominant mutations in GRHL3 cause Van der Woude Syndrome and disrupt oral periderm development. PMID:24360809
• PLoS One • 2016 • Lack of Association between Missense Variants in GRHL3 (rs2486668 and rs545809) and Susceptibility to Non-Syndromic Orofacial Clefts in a Han Chinese Population. PMID:27459192
• The Journal of Craniofacial Surgery • 2024 • Rare Congenital Upper Lip Pit. PMID:38861357

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